REGULATION OF ANGIOTENSIN-II TYPE-2 RECEPTOR GENE BY THE PROTEIN-KINASE C-CALCIUM PATHWAY

In the present study, rat angiotensin II type 2 (AT(2)) receptor expre ssion was upregulated in confluence-arrested PC12 cells compared with expression in proliferating cells. Treatment with cycloheximide inhibi ted the increase in mRNA levels in confluent cells. The state of growt h arrest by serum deprivation was associated with increased expression of the AT(2) receptor, which was markedly suppressed by exposure to t he active phorbol ester 12-O-tetradecanoylphorbol 13-acetate and the c alcium ionophore A23187. Similar inhibitions were also observed in myo cytes isolated from neonatal rat heart. The change in AT(2) mRNA level s by serum deprivation was due to the increase in the gene transcripti on rate. The effect of 12-O-tetradecanoylphorbol 13-acetate was mediat ed through decreases in gene transcription and mRNA stability, whereas A23187 affected mRNA stability. Vasoactive substances with the protei n kinase C-calcium pathway, such as norepinephrine and angiotensin II, also downregulated the AT(1) mRNA level in myocytes. These findings i ndicate that the expression of AT(2) receptor in PC12 cells is regulat ed in a growth state-dependent manner, which is involved in confluence -induced new protein synthesis, thus providing a means by which cells can modulate their responsiveness to external angiotensin II stimulus. The activation of protein kinase C or calcium mobilization modifies t his regulatory mechanism, suggesting that neurotransmitters or vasoact ive substances with the protein kinase C-calcium pathway at least in p art affect neuronal activity or blood pressure control by downregulati ng AT(2) receptor expression.